Human invariant Natural Killer T (iNKT) cells are a group of T cells that have a restricted usage of invariant Vα24-Jα18 T-cell receptor (TCR) and express several cell surface proteins found on Natural killer (NK) cells (Porcelli et al., 1993). iNKT cells share functional and phenotypic homology with both Natural Killer (NK) cells and T cells (FIG. 16). iNKT cells are restricted by the non-polymorphic class Ib molecule CD1d through presentation of glycolipid antigen (Naidenko et al., 1999), resulting in burst secretion of several cytokines, in particular IL-4 and INF-γ (Wilson et al., 2000). The rapid secretion of cytokines implies that iNKT cell may play an important role in modulating the upcoming immune responses and immunopathology. They regulate tumor immunity (Moodycliffe et al., 2000), diabetes (Naumov et al., 2001; Sharif et al., 2001; Wilson et al., 1998), and protection against bacteria (Behar et al., 1999), virus (Kakimi et al., 2000), and parasitic infections (Gonzalez-Aseguinolaza et al., 2000).
iNKT cells have been shown to promote peripheral tolerance in a number of model systems, but their regulatory effects remains poorly understood. Hegde et al. showed that soluble factors secreted by human iNKT cells instruct human peripheral blood monocytes to differentiate into myeloid APCs that have suppressive properties. Additionally, human iNKT cells direct primary human peripheral blood monocytes to differentiate into cells resembling immature myeloid Dendritic Cells (DC) (Hedge et al., 2007). iNKT cell activation by recognition of CD1d expressed on monocytes resulted in secretion of GM-CSF and IL-13 which promoted monocyte differentiation. The resulting myeloid cells showed up-regulation of DC-SIGN, little or no expression of CD14, and moderate expression of co-stimulatory markers, CD40 and CD86, and thus had a cell surface phenotype consistent with that of immature myeloid DC. Furthermore they revealed localization of MHC class II molecules in LAMP-1+ intracellular vesicles as is characteristic of immature myeloid DC. When exposed to lipopolysaccharide (LPS), immature myeloid DC underwent changes associated with DC maturation, including up-regulation of CD83 and CCR7, and relocation of MHC class II molecules to the cell surface (Hedge et al., 2007). Importantly, DC fails to mature normally in both human and rodent autoimmune diabetes. Furthermore, transfer of highly mature DC protects NOD mice from disease. Therefore, defects in antigen presenting cells and CD1d-restricted T cells may cause the development of pathogenic autoimmune T cells and type 1 diabetes. It is believed that disease progression is influenced by a fine-balance where a TH1-like response is critical for β cell destruction and movement towards overt disease; whereas, if the autoimmune T cell pool becomes biased towards TH2-like cells (e.g., that can inhibit TH1 cells via IL-4 or IL-10), either naturally or by activation or transfer of the appropriate CD1d-restricted T cell subset, the disease process may be halted.
DC is a key mediator of adaptive immunity. In the absence of infection, DC in peripheral tissues is resting in an immature state with limited ability to stimulate naïve T cells. However, after infection, DC undergo maturation, a process characterized by phenotypic changes resulting in improved ability to promote T cell responses. DC maturation can be induced by direct stimulation through DC expressed TLRs, or indirectly by exposure to cytokines released by local immune or nonimmune cells stimulated via their own TLRs. iNKT cells can promote enhanced T cell responses when activated by a powerful stimulus such as the synthetic glycolipid, α-Galactosylceramide (α-GalCer), implying that they can provide all of the signals required for DC activation (Hermans et al., 2007). The mechanisms controlling the generation of a proinflammatory DC as opposed to tolerogenic DC is critical in the development and progression of autoimmune diseases.
Steinman and co-workers have proposed that in the absence of infection or inflammation, there is a steady state flux of immature DC that capture and process endogenous antigens (Steinman et al., 2002). These DC then define immunologic self-tolerance by way of specifically silencing autoreactive T cells and promoting the development of regulatory T cells (Jonuleit et al., 2000). While immature DC appear to harbor the ability to tolerate self and foreign antigens, there are many recent examples of DC differentiated both in vivo and in vitro with potent tolerogenic capacity (Hedge et al., 2007; Albert et al., 2001). Importantly, the Bluestone group recently demonstrated that in vivo, regulatory T cells (Treg) directly interacted with dendritic cells bearing islet antigen and that this preceded the inhibition of T helper cell activation by DC (Tang et al., 2006). The explanation for these apparently contradictory functions appears to lie in the remarkable capacity of immature dendritic cells to differentiate into specific functional subtypes during maturation (Banchereau et al., 2000). Depending on the lineage (i.e. myeloid or lymphoid) and maturation stimulus, DC potently control T cell effector function and cytokine profiles (Rissoan et al., 1999; Liu et al., 2001). The exchange of information between DC and T cells is not unilateral. While DC are required for the efficient priming of antigen-specific lymphocyte responses, T cells in turn are also required for optimal DC maturation (Rissoan et al., 1999). Several investigations, including our own, have underscored the regulatory importance of DC/iNKT cell cross talk in shaping the immune response and controlling the relative percentage of DC subsets (Hedge et al., 2007; Kitamura et al., 1999). Autoreactive iNKT cells have also recently been shown directly to potently induce DC maturation, and mature DC that had been exposed to iNKT cells produced more IL-10 than IL-12, a phenotype consistent with a tolerogenic function (Vincent et al., 2002).